delta Opioid receptor

Opioid receptor, delta 1

Rendering based on PDB 1OZC.
Identifiers
Symbols OPRD1; OPRD
External IDs OMIM165195 MGI97438 HomoloGene20252 IUPHAR: δ GeneCards: OPRD1 Gene
RNA expression pattern
PBB GE OPRD1 207792 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4985 18386
Ensembl ENSG00000116329 ENSMUSG00000050511
UniProt P41143 P32300
RefSeq (mRNA) NM_000911.3 NM_013622.3
RefSeq (protein) NP_000902.3 NP_038650.3
Location (UCSC) Chr 1:
29.14 – 29.19 Mb
Chr 4:
131.67 – 131.7 Mb
PubMed search [1] [2]

The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.[1]

Contents

Function

Activation of delta receptors produces some analgesia, although less than that of mu-opioid agonists.[2] Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.[3]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep,[4] but in tests on mice the non-peptide delta agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg.[5] In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent mu-opioid agonist alfentanil, without affecting pain relief.[6] It thus seems likely that while delta opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the mu agonists currently used for pain relief.

Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects[7] and also upregulation of BDNF production in the brain in animal models of depression.[8] These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors,[9] and so can also be produced by enkephalinase inhibitors such as RB-101.[10]

Recent work indicates that exogenous ligands that activate the delta receptors mimic the phenomenon known as ischemic preconditioning.[11] Experimentally, if short periods of transient ischemia are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then effected. Opiates and opioids with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection.[12]

Ligands

Until comparatively recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors for which selective ligands have long been available.

However there are now several selective delta opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80,[13] the more potent (+)-BW373U86,[14] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,[15] and the mixed mu/delta agonist DPI-3290, which is a much more potent analgesic than the more highly selective delta agonists.[16] Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole.[17]

Delta opioid ligands.png

Agonists

Peptides
Non-peptides

Mitragyna Speciosa(aka Kratom) Indole Agonists:

Antagonists

Interactions

Delta opioid receptors have been shown to interact with beta-2 adrenergic receptors,[19] arrestin beta 1[20] and GPRASP1.[21]

References

  1. ^ Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, Slate CA, Ehlert FJ, Roeske WR, Yamamura HI (1999). "The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy". Pharmacol. Rev. 51 (3): 503–32. PMID 10471416. http://pharmrev.aspetjournals.org/content/51/3/503.full. 
  2. ^ Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (2004). "Agonist-specific regulation of the delta-opioid receptor". Life Sci. 76 (6): 599–612. doi:10.1016/j.lfs.2004.07.020. PMID 15567186. 
  3. ^ Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (2006). "The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol". J. Pharmacol. Exp. Ther. 317 (3): 1337–48. doi:10.1124/jpet.105.095810. PMID 16537798. 
  4. ^ Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, Szeto HH (1998). "Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep". Am. J. Obstet. Gynecol. 178 (2): 397–401. doi:10.1016/S0002-9378(98)80032-X. PMID 9500506. http://www.ajog.org/article/S0002-9378(98)80032-X/pdf. 
  5. ^ Gallantine EL, Meert TF (2005). "A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80". Basic Clin. Pharmacol. Toxicol. 97 (1): 39–51. doi:10.1111/j.1742-7843.2005.pto_07.x. PMID 15943758. 
  6. ^ Su YF, McNutt RW, Chang KJ (1998). "Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception". J. Pharmacol. Exp. Ther. 287 (3): 815–23. PMID 9864259. http://jpet.aspetjournals.org/cgi/content/abstract/287/3/815. 
  7. ^ Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH (2002). "Behavioral effects of delta-opioid receptor agonists: potential antidepressants?". Jpn. J. Pharmacol. 90 (1): 1–6. doi:10.1254/jjp.90.1. PMID 12396021. 
  8. ^ Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH (2006). "Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats". Brain Res. 1069 (1): 172–81. doi:10.1016/j.brainres.2005.11.005. PMC 1780167. PMID 16364263. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1780167. 
  9. ^ Zhang H, Torregrossa MM, Jutkiewicz EM, Shi YG, Rice KC, Woods JH, Watson SJ, Ko MC (2006). "Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects". Eur. J. Neurosci. 23 (4): 984–94. doi:10.1111/j.1460-9568.2006.04621.x. PMC 1462954. PMID 16519663. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1462954. 
  10. ^ Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH (2006). "Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects". Eur. J. Pharmacol. 531 (1-3): 151–9. doi:10.1016/j.ejphar.2005.12.002. PMC 1828120. PMID 16442521. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1828120. 
  11. ^ Zhang J, Qian H, Zhao P, Hong SS, Xia Y (2006). "Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor". Stroke 37 (4): 1094–9. doi:10.1161/01.STR.0000206444.29930.18. PMID 16514101. 
  12. ^ Guo L, Zhang L, Zhang DC (2005). "[Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications]" (in Chinese). Sheng li ke xue jin zhan [Progress in physiology] 36 (4): 333–6. PMID 16408774. 
  13. ^ Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC (1994). "Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist". J. Med. Chem. 37 (14): 2125–8. doi:10.1021/jm00040a002. PMID 8035418. 
  14. ^ Calderon SN, Rice KC, Rothman RB, Porreca F, Flippen-Anderson JL, Kayakiri H, Xu H, Becketts K, Smith LE, Bilsky EJ, Davis P, Horvath R (1997). "Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands". J. Med. Chem. 40 (5): 695–704. doi:10.1021/jm960319n. PMID 9057856. 
  15. ^ Jutkiewicz EM (2006). "The antidepressant -like effects of delta-opioid receptor agonists". Mol. Interv. 6 (3): 162–9. doi:10.1124/mi.6.3.7. PMID 16809477. 
  16. ^ Ananthan S (2006). "Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics". AAPS J 8 (1): E118–25. doi:10.1208/aapsj080114. PMC 2751430. PMID 16584118. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2751430. 
  17. ^ Portoghese PS, Sultana M, Takemori AE (1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". Eur. J. Pharmacol. 146 (1): 185–6. doi:10.1016/0014-2999(88)90502-X. PMID 2832195. 
  18. ^ Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (October 2008). "Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)". Journal of Medicinal Chemistry 51 (19): 5893–6. doi:10.1021/jm8008986. PMID 18788723. 
  19. ^ McVey, M; Ramsay D, Kellett E, Rees S, Wilson S, Pope A J, Milligan G (Apr. 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". J. Biol. Chem. (United States) 276 (17): 14092–9. doi:10.1074/jbc.M008902200. ISSN 0021-9258. PMID 11278447. 
  20. ^ Cen, B; Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G (Mar. 2001). "Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor". J. Neurochem. (United States) 76 (6): 1887–94. doi:10.1046/j.1471-4159.2001.00204.x. ISSN 0022-3042. PMID 11259507. 
  21. ^ Whistler, Jennifer L; Enquist Johan, Marley Aaron, Fong Jamie, Gladher Fredrik, Tsuruda Pamela, Murray Stephen R, Von Zastrow Mark (Jul. 2002). "Modulation of postendocytic sorting of G protein-coupled receptors". Science (United States) 297 (5581): 615–20. doi:10.1126/science.1073308. PMID 12142540. 

Further reading

External links


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